The intestinal apparatus is affected by many inflammatory diseases generally capped as inflammatory bowel diseases. In particular, Crohn's disease is a severe chronic inflammatory disease affecting various levels of the digestive tract, from the mouth to the anus, particularly it can be observed in the last portion of the small intestine, either the ileum, the colon or both and sometimes in the mucous membrane of the colon and in the anal region as well. In the interested intestinal part, inflammation, swelling and ulceration occur in the whole intestinal wall causing stenosis, bleeding ulcers and pain, while the non-affected tissue portions appear normal. Crohn's disease exhibits alternate periods of inflammatory symptoms of variable gravity with symptoms such as: diarrhea, abdominal pain, weight loss often accompanied by rhagades or peri-rectal fistulas. From two-thirds to three-quarters of patients with Crohn's disease require surgery at some point in their lives. Surgery is used either to relieve symptoms that do not respond to medical therapy or to correct complications such as blockage, perforation, abscess, or bleeding in the intestine.
The role of the intestinal bacterial flora in the etiopathogenesis of the intestinal inflammatory diseases and in particular in Crohn's disease is evidenced by, for example, the frequency of localization to areas with high bacteria concentrations, see Jannowitz, H. D., in Inflamm. Bowel Dis., 1998, 44, 29-39; the deviation of the faecal flow determines remission of the endoscopic damages which reappear again at restoration of the canalisation, see Rutgeerts, P., in Lancet, 1991, 338, 771-774; experimental models, e.g., knock-out mouse for the IL-10 gene or others, show that spontaneous colitis does not develop if a “germ-free” condition is maintained, see Blumberg R. S., in Curr. Opin. Immunol., 1999, 11(6), 648-56; inflammation of intestinal mucous membrane develops after the contact with faecal material, see Harper P. H., in Gut 1985, 26(3), 279-84; after surgical “curative” therapy consisting of ileocolic anastomosis, antibiotic treatment delays the development of both endoscopic and clinic relapses, see Cameron J. L. in Ann Surg., 1992, 215, 546-52; and the presence of fistulae or abscess-sacs points out further the bacterial contribution to the disease development.
Crohn's disease has previously been treated with drugs that are able to decrease or control the inflammation, e.g., cortisones, salazopirine, mesalazine, immunosupressants, specific chemotherapeutics, antibiotics and protein inhibitors of the actions of the Tumor Necrosis Factor (TNF). During the treatment of the acute phase of the inflammatory bowel disease, stronger treatments are often necessary to ensure parenteral alimentation, to reconstitute the loss of proteins, liquids and salts, to permit the intestine to rest to facilitate the cicatrisation of ulcers. The purpose of the therapy is to decrease the frequency of the reappearance of symptoms and to reduce the seriousness acute episodes when they appear. However, with current therapies, acute episodes respond in about 50-70% of the cases, but relapses occur in 80% of the patients.
Antibiotics are usually used to decrease the growth of the luminal bacteria; to decrease the inflammatory state sustained as a result of the bacterial growth; to reduce symptoms of the acute phase of the disease, e.g., diarrhea, intestinal pain and meteorism; and to prevent and to cure septic complications, e.g., abscesses, fistulas and toxic state.
The most frequently used antibiotics are systemically absorbed, for example, metronidazole (active against some parasites along with many anaerobic bacteria) and ciprofloxacin (active against such bacteria as E. Coli and aerobic enterobacteriace). Metronidrazol has been used at a dose of 10-20 mg/kg/day for 4 months (Sunterland, L. Gut, 199132, 1071-5), while ciprofloxacin has been used at a dose of 1000 mg/day for 6 weeks (Colombel J. F. in Am. J. Gastoenterol., 1999, 94, 674-8), while Prantera in Am. J. Gastoenterol., 1996, 91, 328-32, adopted the combination of the two antibiotics using metronidazole at the dose of 1000 mg/day and ciprofloxacin at the dose of 1000 mg/day for 12 weeks. The high systemic bioavailability of these antibiotics is at the root of their high incidence of side effects registered in long-term therapies, which negatively impacts their use. The incidence of side effects in the use of metronidazole ranges from 10% to 20%, depending on the dose and the treatment duration. The most frequent side-effects include metallic taste, gastric intolerance, nausea, glossitis, cephalea, vertigo, ataxia, convulsion and neurotoxicity. Peripheral neuropathy has been recorded in 50-85% of the long-term treated patients, which may regresses only after several months of therapeutic interruption. The percentage of side effects described in ciprofloxacin studies is variable and depends in part on the dosage and the duration of the treatment. The most frequent of the side effects are of gastrointestinal origin, but an increase of the transaminase and skin reactions have also been frequently described. Thus, there is a need in the art for a long-term treatment option for inflammatory diseases of the digestive tract, e.g., gastro enteric pathologies.